(Tumorgenesis and Genes)
Individual tumors exhibit distinct characteristic natures, and their biological properties are not necessarily identical even though the basic principle of oncogenesis is the same. Rapid advances in the understanding of cancer from a molecular biological and molecular genetic perspective in recent years have opened the way to an explanation of oncogenesis and the so-called tumor cell biology on the genetic level.
(Neuroblastoma)
Neuroblastoma is a pediatric cancer occurring in sympathetic gangliocytes and adrenal medullary cells which originate from cells of the peripheral sympathetic nervous system. Of these sympathetic neurons, neural crest cells in the initial stage of development migrate to the abdomen, differentiating and maturing at sites where sympathetic ganglia are formed. Some of these cells migrate further to the adrenal bodies, penetrating through the adrenal cortex which is already in the process of formation, and reaching the medulla and forming medullary substance there. The neural crest cells also serve as a source of other peripheral nerve cells, differentiating into dorsal root ganglia (sensory nerves), skin pigment cells, thyroid C cells, some pulmonary cells, intestinal gangliocytes, and the like.
(Prognosis for Neuroblastoma)
Neuroblastoma is characterized by a varied clinical profile (Nakagawara, Shinkeigashu no Hassei to Sono Bunshi Kiko [Neuroblastoma Development and Molecular Mechanism], Shoni Naika [Japanese Journal of Pediatric Medicine], Vol. 30, p. 143, 1998). For example, neuroblastoma occurring at less than one year of age has very favorable prognosis, with the majority undergoing differentiation and cell death, and results in spontaneous regression (which may be referred to as “favorable prognosis type”). Currently, most neuroblastomas discovered by a positive result in the commonly performed mass screening of 6-month-old infant urine are of the type which tend to undergo this spontaneous regression. On the other hand, neuroblastoma occurring at age 1 or higher is highly malignant and leads to death of the infant in the majority of cases despite therapy (which may be referred to as “unfavorable prognosis type”). It is also hypothesized that a somatic mutation occurs in highly malignant neuroblastomas in infants older than one year of age, which are of monoclonal nature, whereas in naturally regressing neuroblastomas, the genetic mutation remains at only a germ line mutation. See Knudson A G, et al.: Regression of neuroblastoma IV-S: A genetic hypothesis, N. Engl. J. Med., Vol. 302, p. 1254, 1980. In addition, there are known neuroblastomas of the intermediate type that are clinically positioned between those two types.
When the neuroblastomas are classified according to the progress of tumorization, they are as follows:    Stage 1: the tumor occurs primarily in adrenal gland or sympathetic ganglia and is confined.    Stage 2: the tumor is characterized by being confined to the site of origin and regional metastasis only to lymph nodes, which does not extends beyond the median line.    Stage 3: the tumor extends beyond the median line to invade into the opposite side or to metastasize into lymph nodes.    Stage 4: the tumor causes distant metastasis to bone, bone marrow or the orbital region.    Stage 4s: the tumor occurs at less than one year of age and causes distant metastasis to bone marrow, skin or liver.
The neuroblastomas of the favorable prognosis type are tumors at stages 1, 2, and 4s, while the neuroblastomas of the unfavorable and intermediate types are tumors at stages 3 and 4. The tumor at stage 4s is peculiar and normally occurs in an infant at several months after birth. Although the tumor grows and metastasizes quickly, it suddenly stops growing and then disappears spontaneously. Thus, the tumors that regress spontaneously and the tumors that grow malignantly are clearly distinct, with respect to the age of onset, the site of metastasis, and the progress.
(Genes which Allow the Prediction of Prognosis for Neuroblastoma)
With recent advances in molecular biology research, it has become clear that expression of the high affinity nerve growth factor (NGF) receptor TrkA is closely connected with control of differentiation and cell death (see Nakagawara A., The NGF story and neuroblastoma, Med. Pediatr. Oncol., vol. 31, p. 113, 1998). Trk is a membrane-spanning receptor, existing as the three major types, Trk-A, -B and -C.
These Trk family receptors play an important role in specific nerve cell differentiation and survival in the central nervous and peripheral nervous systems (see Nakagawara, et al., Shinkeigasaiboushu ni Okeru Neurotrophin Juyoutai no Hatsugen to Yogo [Expression of Neurotrophin Receptors and Prognosis in Neuroblastoma], Shoni Geka (Japanese Journal of Pediatric Surgery), Vol. 29, pp. 425-432, 1997). The survival and differentiation of tumor cells is controlled by signals from Trk tyrosine kinase and Ret tyrosine kinase. In particular, the role of TrkA receptor is most significant, with TrkA expression being notably high in neuroblastomas of the favorable prognosis type, and its signals exerting a powerful control over the survival and differentiation of tumor cells, and cell death (apoptosis). In neuroblastomas of the unfavorable prognosis type, on the other hand, TrkA expression is significantly suppressed, while tumor development is aided by a mechanism in which survival is promoted by signals from TrkB and Ret, instead.
It has become clear that amplification of the neural oncogene N-myc is associated with the prognosis of neuroblastoma (see Nakagawara, Nou-shinkeishuyo no Tadankai Hatsugan [Multistage Oncogenesis of Cerebral and Neural Tumors], Molecular Medicine, Vol. 364, p. 366, 1999). This gene, first cloned in neuroblastoma, is ordinarily only present in a single copy per haploid set in normal cells and neuroblastomas of the favorable prognosis type, whereas it has been found to be amplified several dozen times in neuroblastomas of the unfavorable prognosis type.
In addition to the genes described above, CD44, PTN, caspase and others are known as the gene whose expression is high in neuroblastomas of the favorable prognosis type, whereas SVV (survivin), MK (midkine) and others are known as the gene whose expression is high in neuroblastomas of the unfavorable prognosis type.
Furthermore, the present inventors found that a group of novel genes was highly expressed in neuroblastomas of the favorable prognosis type (International Publication PCT/JP01631 pamphlet). By contrast, the present inventors found that a different group of novel genes was highly expressed in neuroblastomas of the unfavorable prognosis type (International Publication PCT/JP01629 pamphlet).
Up till the present time, however, there has hardly been any information concerning the genes which are expressed in stage 4s neuroblastoma, particularly with specificity. Further, since stage 4s neuroblastoma regresses spontaneously, there is an urgent need to identify the causative genes.